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PHOSPHATIDYLINOSITOL SIGNALING AND HUMAN DISEASE

磷脂酰肌醇信号传导与人类疾病

基本信息

批准号：
7860438
负责人：
PHILIP W MAJERUS
金额：
$ 114.41万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860438
关键词：
Adipocytes Animals Apoptosis Biochemistry Biological Blood Cells Blood Platelets Cell Differentiation process Cell physiology Cells Defect Development Disease Embryo Enzymes Family Fetal Liver Folate Functional disorder Future Genotype Health Inositol Inositol Metabolism Pathway Inositol Phosphate Metabolism Pathway Inositol Phosphates Joubert syndrome Laboratories Laser injury Lead Learning Life Lipids Mammals Modeling Mus Mutant Strains Mice Mutation Mutation Analysis Myocardial Infarction Nerve Degeneration Neural Tube Defects Pathogenesis Pathway interactions Patients Phenotype Phosphatidylinositols Phospholipids Phosphorylation Phosphotransferases Phytic Acid Play Polyphosphates Post-Translational Protein Processing Prevention Production Protein Kinase Proteins RNA Interference Radiation Reaction Relative (related person)Resistance Role Signal Pathway Signal Transduction Stress Stroke Supplementation Syndrome Thrombosis Uncertainty Work adipocyte differentiation base human disease in vivo inositol-1,4,5-trisphosphate 5-phosphatase liver transplantation mouse model mutant myotubularin overexpression phosphoinositide-3,4-bisphosphate prevent research study

项目摘要

This project aims to define the roles of inositol signaling reactions in the pathogenesis of disease. We will study the role of inositol 1,3,4-5/6-kinase in fat cell differentiation. This enzyme catalyzes the first step in formation of inositol hexakisphosphate (IP6) which is essential for life in mammals. Preliminary studies indicate that the enzyme and others leading to IP6 production are highly expressed during fat cell differentiation and that some metabolite in this pathway may actually cause fat cell development. We will use overexpression and RNAi studies to define the causal molecule. In another study we plan to determine the potentially prothrombotic phenotype of mice with elevated levels of PI(3,4)P2. We propose that the elevated levels arise from deficiency of 4-ptaseI that occur in Weeble mutant mice. We have made radiation chimeric mice from lethally irradiated normal mice rescued by fetal liver transplants from Weeble embryos. Thus the Weeble mutation is restricted to blood cells and preliminary experiments suggest that these animals have a thrombotic phenotype. We will study platelet function and in vivo thrombosis in a laser injury model. We will investigate the functions of a little studied sub branch of the myotubularin PI 3-ptase family namely MTMR6, MTMR7, MTMR8 and their inactive partner MTMR9. These proteins play undefined roles in stress-induced apoptosis. We recently learned that mutations in another enzyme discovered in our lab are the cause of a severe neurodegeneration Jobert syndrome. The enzyme is inositol polyphosphate 5-phosphataseIV a lipid specific 5-PtaseIV. Dr Jos Gleeson (UCSD/HHMI) has found 5 different mutations in families with Joubert syndrome and has sent us cells and constructs to define the biological consequences of these mutations. In summary we use inositol biochemistry to determine the phenotype vs genotype of disorders of inositol metabolism.

本计画旨在探讨肌醇信号反应在疾病发生机制中所扮演的角色。我们将研究肌醇1，3，4 -5/6-激酶在脂肪细胞分化中的作用。这种酶催化肌醇六磷酸（IP 6）形成的第一步，这是哺乳动物生命所必需的。初步研究表明，导致IP 6产生的酶和其他酶在脂肪细胞分化期间高度表达，并且该途径中的一些代谢物实际上可能导致脂肪细胞发育。我们将使用过表达和RNAi研究来确定致病分子。在另一项研究中，我们计划确定PI（3，4）P2水平升高的小鼠的潜在促血栓形成表型。我们认为，升高的水平引起的缺陷4-ptaseI发生在Weeble突变小鼠。我们已经从Weeble胚胎的胎肝移植挽救的致命辐射正常小鼠中制造了辐射嵌合小鼠。因此，Weeble突变仅限于血细胞，初步实验表明这些动物具有血栓形成表型。我们将在激光损伤模型中研究血小板功能和体内血栓形成。我们将研究肌管蛋白PI 3-磷酸酶家族的一个研究较少的亚分支，即MTMR 6、MTMR 7、MTMR 8和它们的无活性伴侣MTMR 9的功能。这些蛋白质在应激诱导的细胞凋亡中起着不确定的作用。我们最近了解到，我们实验室发现的另一种酶的突变是严重神经变性Jobert综合征的原因。该酶是肌醇多磷酸5-磷酸酶IV，一种脂质特异性5-磷酸酶IV。乔斯·格里森博士（加州大学圣地亚哥分校/HHMI）在朱伯特综合征家族中发现了5种不同的突变，并向我们发送了细胞和构建体来定义这些突变的生物学后果。总之，我们使用肌醇生物化学来确定肌醇代谢障碍的表型与基因型。

项目成果

期刊论文数量（120）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta.

DOI：
10.1083/jcb.101.2.363
发表时间：
1985-08
期刊：
The Journal of cell biology
影响因子：
0
作者：
Maruyama I;Bell CE;Majerus PW
通讯作者：
Majerus PW

Heparin cofactor II. Purification and properties of a heparin-dependent inhibitor of thrombin in human plasma.

DOI：
10.1016/s0021-9258(18)34900-7
发表时间：
1982-03
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
D. Tollefsen;D. Majerus;M. Blank
通讯作者：
D. Tollefsen;D. Majerus;M. Blank

Human coagulation factor Va is a cofactor for the activation of protein C.

人凝血因子 Va 是激活蛋白 C 的辅助因子。

DOI：
10.1073/pnas.80.6.1584
发表时间：
1983
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Salem,HH;Broze,GJ;Miletich,JP;Majerus,PW
通讯作者：
Majerus,PW

Cloning, heterologous expression, and chromosomal localization of human inositol polyphosphate 1-phosphatase.

人肌醇多磷酸1-磷酸酶的克隆、异源表达和染色体定位。

DOI：
10.1073/pnas.90.12.5833
发表时间：
1993
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
York,JD;Veile,RA;Donis-Keller,H;Majerus,PW
通讯作者：
Majerus,PW

The structure and function of mouse thrombomodulin. Phorbol myristate acetate stimulates degradation and synthesis of thrombomodulin without affecting mRNA levels in hemangioma cells.

小鼠血栓调节蛋白的结构和功能。